Estrogenic hormones are now recognized to modulate normal immune system function and mounting evidence indicates that they influence the incidence and course of human autoimmune diseases. Some of these autoimmune diseases, while they occur predominantly in women, tend to appear in the menopause, when hormonal output from the ovary is waning. Rheumatoid arthritis, in particular, is a disorder of older women, and is accompanied by alterations of immune system function that might be impacted by estrogens. We propose to investigate the effects of estrogens on immune system function in the setting of the menopause. We propose to test the hypothesis that estrogens alter thymic output of T cells in menopausal women. We will use real time polymerase chain reaction amplification of T cell receptor excision circle DMA from peripheral blood cells to quantitate recent thymic emigrants in menopausal women before and after estrogen replacement therapy. We will use flow cytometric techniques to quantitate naive T cells in the same subjects. We propose to test the hypothesis that estrogens alter the course of proliferative senescence of T cells. T cell telomere length and telomerase activity will be assessed in menopausal women before and after estrogen replacement therapy. In vitro experiments will assess the effect of estrogens on T cell telomerase activity and explore the mechanisms of estrogenic regulation of telomerase in peripheral T cells PUBLIC HEALTH RELEVANCE: These studies will explore the influence of ovarian hormones on the aging immune system. The findings will expand our knowledge of interactions between the endocrine and immune systems and their alterations in aging. The findings will help us understand whether declining ovarian function in the menopause might contribute to the increased risk for autoimmune diseases such as rheumatoid arthritis. [unreadable] [unreadable] [unreadable]